Previously known processes for preparing bisphosphonic acids involved hydrolysing the corresponding tetraesters using strong acids, such as halogen acids. Thus, for example, the isopropyl tetraester has been boiled for several hours with concentrated hydrochloric acid. The publication Houben-Weyl, Methoden der Organischen Chemie, XII. 1,352-356 describes the hydrolysis of tetraesters with half-concentrated hydrochloric acid under elevated pressure and at 130-145xc2x0 C. The disadvantage of these processes is the impurities in the products and the numerous purification steps needed to remove by-products and excess acid.
EP0200980 describes a process in which methylene bisphosphonic acids were prepared by hydrolysing tetraesters with water, by boiling at reflux temperature of the reaction mixture. Whilst problems of impurities of corrosion were largely overcome, the reaction time was very long, as long as 16 hours, which is disadvantageous for commercial production.
The hydrolysis of the tetraester disclosed in WO91/103480 is performed using from 1.0 to 5% by weight hydrochloric acid. Active charcoal is required to decolourise the solution.
GB 1026366 describes the preparation of the tetrasodium salt of dichloromethylenebisphosphonic acid by refluxing dichloromethylene bisphosphonate tetraisopropyl ester with concentrated hydrochloric acid. The acidic solution was concentrated and twice azeotroped with isopropanol. Neutralisation of the acid with sodium hydroxide yielded the tetrasodium salt.
It has now been found that the salt formed from the acid which in turn is formed by hydrolysing a substituted or unsubstituted ester of methylene bisphosphonic acid with 15 to 20% by weight hydrochloric acid, followed by the azeotropic removal of water using n-butanol, can be easily isolated in a good yield and has far fewer impurities.
According to a first aspect of the invention there is provided a process for preparing salts of substituted or unsubstituted methylene bisphosphonic acids of general formula I, 
wherein X1 and X2 are independently hydrogen or halogen, which process comprises hydrolysing, using hydrochloric acid, the corresponding ester of formula II, 
wherein X1 and X2 are defined above and R is a C1-4 straight or branched alkyl group and converting the acid to a salt by reaction with a base characterised in that the concentration of hydrochloric acid is from 15% to 20% by weight, and water is removed azeotropically from the resultant acid using n-butanol prior to the addition of an amine or a base.
Preferably X1 and X2 are both fluorine, chlorine or bromine.
Most preferably X1 and X2 are both chlorine.
The tetraester of formula II is preferably the isopropyl ester such as dichloromethylene bisphosphonate tetraisopropyl ester.
The acid product of the hydrolysis may be reacted with an organic or inorganic base such as a C1-6 straight or branched primary, secondary or tertiary alkylamine, aralkyl amine. basic N-containing heterocycle, alkali or alkaline earth metal hydroxides.
The preferred bases are C1-4 straight or branched and primary, secondary or tertiary alkyl amines, aralkyl amines, basic N-containing heterocycle, or alkali metal hydroxides.
Suitable bases may be selected from the group comprising triethylamine, tri-n-propylamine, diisopropylethylamine, tri-n-butylamine, pyridine, tribenzylamine and sodium hydroxide.
The volume of hydrochloric acid used is from 3 to 5 volumes and the hydrolysis using the acid is preferably carried out at a temperature of about 80xc2x0 C. to about 90xc2x0 C. Following the addition of n-butanol a vacuum is suitably applied.
Thus in a preferred process according to the invention an ester of methylenebisphosphonic acid, such as dichloromethylene bisphosphonate tetraisopropyl ester, is dissolved in from about 15% to about 20% hydrochloric acid, preferably about 18% hydrochloric acid. The resultant solution is added dropwise to a stirred solution of 15% to 18% hydrochloric acid which has been heated to a temperature of from about 80xc2x0 C. to about 90xc2x0 C., preferably about 85xc2x0 C. The total volume of acid used is in the range of from about 3 to about 5 volumes, preferably about 4 volumes. The solution is then stirred at the elevated temperature for from about 1 to about 3 hours, preferably about 2 hours, under a flow of nitrogen, whilst collecting the distillate. After this time the solution is heated to get a steady flow of distillate. Further water is added to the hot reaction mixture and then further solvent removed by distillation.
The reaction mixture is then cooled prior to the addition of n-butanol. Vacuum and heat are then applied to the vessel. Distillate is removed whilst periodically adding n-butanol. An n-butanol solution of the dichloromethylene bisphosphonic acid is then obtained. The solution may then be diluted with n-butanol and another alcohol if desired. To this solution is added the amine or base and the reaction mixture is stirred. For the mono(tri-n-butylamine)salt crystallisation typically begins within 30 minutes, while many others precipitate more rapidly. The suspension is then filtered and the solid washed with n-butanol. The damp solid is dried in vacuo to give the dichloromethylene bisphosphonic acid salt in high yield.
Use of hydrochloric acid within the defined range of concentration in the process of the invention has the advantage that the hydrolysis can be completed within 2 hours. No analytical method is required to follow the reaction and no purification with for example charcoal, is required.
The azeotropic removal of water using n-butanol results in a far superior removal of water than isopropanol. It also has the advantage of producing the end product in better yields as small amounts of water can have a significant effect on the crystallisation of the salt.
The use of vacuum lowers the azeotropic boiling point for water/n-butanol mixtures. The amount of water removed is also increased which reduces processing time. Thus the use of vacuum speeds up the removal of water and the control of temperature limits impurity formation.
According to a second aspect of the invention there is provided a salt of a substituted or unsubstituted methylene bisphosphonic acid of formula I wherein X1 and X2 are independently hydrogen or halogen. Preferably X1 and X2 are both hydrogen, fluorine, chlorine or bromine, most preferably X1 and X2 are both chlorine. Alternatively, one of X1 and X2 is hydrogen and one is chlorine.
The salt may be a C1-6 straight or branched primary, secondary or tertiary alkyl amine salt, an aralkly amine salt, a basic N-containing heterocycle salt, an alkali or alkaline earth metal salt.
Preferably the salt is a C1-4 straight or branched primary, secondary or tertiary alkylamine salt an aralkyl amine salt, a basic N-containing heterocycle salt or an alkali metal salt such as sodium or potassium salt.
Most preferably the salt is a triethylamine, tri-n-propylamine, diisopropylethylamine, tri-n-butylamine, pyridine, tribenzylamine or sodium salt. The sodium salt may be the di-, tri- or tetrasodium salt.
The process of the invention will be described in more detail by way of reference to the following non-limiting examples: